Persistent atrial fibrillation (AF) represents a major public health and medical challenge. The progressive nature of the disease, high morbidity, and increasing health-economic costs ensure that it remains at the forefront of novel research into mechanisms and potential therapies. These are largely divided into pharmacological (drugs) and electrical (ablation) with patients often going from former to latter. AF ablation has improved sufficiently to be offered as first line for paroxysmal AF, but whether drug therapy will or be relegated. In this review, we shall outline the progress in mechanistic understanding of AF that may allow results from ablation to diverge dramatically from drug therapy and identify populations in whom drug therapy may become less relevant. We end by looking ahead to future developments that we hope will spur on therapeutic efficacy in both fields.